Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor neurons of the spinal cord and brain. Degeneration of spinal motor neurons leads to muscular atrophy and weakness, while degeneration of motor neurons in the cerebral cortex leads to hyperreflexia. ALS is rapidly progressive; patients generally die within two to five years of onset. The annual incidence rate of ALS is one to two per 100,000. This rate increases with age and is greater in men than in women. Approximately 5 to 10% of ALS cases have a family history of ALS. In general, the etiology of ALS remains unclear, although genetic factors are involved in the familial form. Environmental exposures have also been considered as potential causes of ALS. Existing evidence has most clearly suggested a role for exposure to heavy metals, particularly lead, although electromagnetic fields and chemical exposures including pesticides and solvents have also been implicated. We conducted a case-control study of ALS in New England from 1993 to 1996. The primary purpose of the study was to evaluate the relationship of lead exposure to ALS. We collected information on occupational, residential, and recreational exposure to lead using a structured interview. In addition, we measured blood and bone lead levels, the latter via in vivo K x-ray fluorescence (K-XRF). To our knowledge, no previous studies have reported bone lead levels in ALS cases measured with this technique. We evaluated the relation of lead exposure to ALS, using both biological measures and interviews, in a case-control study. Cases (N=109) were recruited at two hospitals in Boston, MA. Population controls (N=256) identified by random digit dialing were frequency-matched to cases by age, sex, and region of residence within New England. Risk of ALS was associated with a two-fold increase in self-reported occupational exposure to lead, with a dose-response for lifetime days of lead exposure. Risk of ALS was also associated with elevations in both blood and bone lead levels. These results are consistent with previous reports and suggest a potential role for lead exposure in the etiology of ALS. We also evaluated the relationship of ALS to genetic susceptibility to lead. The ALAD2 allele was associated with decreased lead levels in both patella and tibia, although not with blood lead levels, and with a two-fold increased risk of ALS. In contrast, the vitamin D receptor B allele was not associated with lead levels or ALS.